The objective of this research plan is to develop an economically feasible therapy for HIV- associated cytomegalovirus retinitis for use in the international community. Using the National Eye Institute?s patent and patent-pending methods of manufacturing intraocular devices, an implant will be developed that will locally release ganciclovir in the eye for a prolonged period of time. BACKGROUND The international community has experienced a dramatic increase in HIV-infection over the last decade. An estimated 40 million persons are infected world-wide with the majority of these persons living in Africa where there social and economic infrastructure of some countries have been devastated.1 Cytomegalovirus (CMV) retinitis resulting from HIV infection is generally a disease of profound immunosuppression and leads to blindness without specific anti-CMV therapy. Without antiretroviral therapy, survival time after the diagnosis of CMV retinitis is less than 1-month and many patients live the remainder of their lives blind in both eyes. Death is most commonly from opportunistic infections such as pneumococcal pneumonia and tuberculosis. In some African countries, there are major initiatives that have increased the life expectancy of HIV-infected persons and these include the use of less than effective mono- or bi- antiretroviral therapy and the prophylactic use of antimicrobials for prevention of opportunistic infections. As a result, HIV-infected persons are living longer and the prevalence of CMV retinitis has increased. Ironically, an epidemic of blindness as a consequence of improved care for HIV-infected persons has occurred in Africa and 10?20% of patients can expect to lose their sight in one or both eyes as a result of CMV retinitis.8, 9 Blindness not only increases the morbidity associated with HIV-infection but also adds to the burden of care for countries with limited resources.8, 10 Systemic therapy of CMV retinitis requires a complex induction?maintenance schedule of administration of ganciclovir or foscarnet through central venous access. The cost of 1-year?s induction?maintenance systemic treatment of CMV retinitis is estimated to be over US$30,000. Since the technology required for systemic administration of anti-CMV therapies is cost-prohibitive, patients in underdeveloped countries are generally not treated and blindness ensues. Local therapy using sustained-release ganciclovir implants were investigated intramurally by the NEI in the 1990?s and found to be an effective therapy for CMV retinitis. Local antiviral therapy using implants does not require intravenous paraphernalia and reduces the costs associated with line infections, home health care, and treatment for systemic antiviral toxicities. Clinical trials14-16 have shown the ganciclovir implant to be more effective than systemic anti-CMV therapy for treating CMV retinitis. As a result, a ganciclovir implant, currently manufactured by Bausch and Lomb, was approved for use in the United States in 1996. The implant surgery takes 20 to 30 minutes, does not require automated machinery, and can be performed by the majority of general ophthalmic surgeons under local anesthesia. Unfortunately, the manufacturing process is complex and the cost of each implant is US$4,400 which is not a reasonable for most underdeveloped countries. The current ganciclovir implant preparation techniques have relied on covering the drug pellet with permeable and impermeable polymers by multi-wet coating and drying approaches. Such wet coating approaches can raise product quality control issues such as an increased risk of delamination of the thinly applied coatings, as well as thickness variability of the polymer around the drug pellets obtained during hardening. Additionally, increased production costs and time from higher implant rejection rates and labor are known problems associated with the present ganciclovir implant technology. In our laboratory, we have developed a simple low-cost manufacturing process for a variety of sustained-release ocular pharmaceutical implants. The patented and patent-pending NEI methods are the basis for a number of NEI CRADAs with pharmaceutical companies including Pharmcia/Pfizer and Merck/Germany. Our implants have been used in a number of preclinical studies and in collaboration with the Pharmaceutical Development Section in the Clinical Center Pharmacy, implants are being manufactured for intramural clinical NEI protocols. Our aim is to develop a cost-effective ocular implant that releases ganciclovir over a 1-year period to treat CMV retinitis in underdeveloped countries. This initiative is consistent with the research priorities of the Office of AIDS Research NIH FY 2004 Plan for HIV-Related research that advocates the development of novel therapeutic interventions for opportunistic infections in the international community.